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Nat Cell Biol. 2017 Jun;19(6):626-638. doi: 10.1038/ncb3527. Epub 2017 May 15.

Regulation of mitochondrial biogenesis in erythropoiesis by mTORC1-mediated protein translation.

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Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Key Laboratory of Computational Biology, Collaborative Innovation Center for Genetics and Developmental Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA.
Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Minister of Education, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.


Advances in genomic profiling present new challenges of explaining how changes in DNA and RNA are translated into proteins linking genotype to phenotype. Here we compare the genome-scale proteomic and transcriptomic changes in human primary haematopoietic stem/progenitor cells and erythroid progenitors, and uncover pathways related to mitochondrial biogenesis enhanced through post-transcriptional regulation. Mitochondrial factors including TFAM and PHB2 are selectively regulated through protein translation during erythroid specification. Depletion of TFAM in erythroid cells alters intracellular metabolism, leading to elevated histone acetylation, deregulated gene expression, and defective mitochondria and erythropoiesis. Mechanistically, mTORC1 signalling is enhanced to promote translation of mitochondria-associated transcripts through TOP-like motifs. Genetic and pharmacological perturbation of mitochondria or mTORC1 specifically impairs erythropoiesis in vitro and in vivo. Our studies support a mechanism for post-transcriptional control of erythroid mitochondria and may have direct relevance to haematologic defects associated with mitochondrial diseases and ageing.

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